The objective of this program project is to study the operative mechanisms and functional consequences of T lymphocyte costimulation and peripheral tolerance. Emphasis is placed on the analysis to tolerance in vivo, in normal T cells, and in human T cells, and in human T cell clones, and on genetic models for dysregulation of costimulators, specifically B7, in vivo. The four interactive projects in the program have the following aims. Project 1. Immunobiology of peripheral T cell tolerance in vivo and in vitro (Abbas) The goals of this project are to define the roles of antigen-presenting cells (APCs), costimulators and cytokines in the induction of tolerance in normal CD4+T cells and in vivo, using mice that express a transgenic T cell receptor (TCR). The sensitivity of different T cell populations to tolerance, and the fates of anergic T cells, will be examined. The mechanisms responsible for the unresponsiveness of CD8+T cells that escape thymic selection will be examined in a TCR transgenic model. Project 3. Role of the B7 costimulatory pathway in the induction of anergy in vivo (Sharpe) The development of anergy, and the fates of antigen-responding T cells, will be examined in mice in which B7 has been deleted by homologous recombination, and in B7 transgenic mice. The consequences of immunization will be compared in B7- mice and in mice treated with B7-specific antagonists. The maturation and functions of TCR transgene into B7- and B7 transgenic mice. Project 4. Intracellular mechanisms of T cell costimulation and anergy (Bierer) The biochemical signals induced by costimulators in mouse and human T cell clones and in normal T cells will be analyzed, with particular emphasis on the role of kinases and transcription factors. The nature of CD28- and CTLA-4-associated proteins will be examined. Based on this information, the biochemical defects in anergic T cells will be defined. Thus, this program explores fundamental questions about the nature and functions of costimulators, the mechanisms of T cell anergy, and the biologic significance of peripheral T cell tolerance.